Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

Abstract

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆4-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆4-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.

Synthesis of 5‐ and 7‐hydroxy indolizidin‐2‐one prostaglandin‐F2α modulators and activity on myometrial contractility towards development of agents for delaying preterm birth

“…The syntheses of mimics 19 and (6 S ,7 S )‐ 8 were respectively achieved using a common approach from the respective carboxylic acids 15 and 16 , which were synthesized according to the protocols described in reference 26 (Scheme 1). Initially, acids 15 and 16 were respectively coupled to (2 S )‐3‐pyridylalaninyl‐(3 S )‐β‐homophenylalanine benzyl ester ( 20 ) 11,12 using TBTU and HOBt to obtain the respective peptides 21 and 22 in 60% and 55% yields.…”

“…Recently, effective syntheses of (3 S ,5 S ,6 S ,9 S )‐Boc‐(5‐hydroxy)I 2 aa‐OH ( 15 ) and (3 S ,6 S ,7 S ,9 S )‐Boc‐(7‐hydroxy)I 2 aa‐OH [ 16 , Figure 3] were achieved by a route involving the construction of a ∆ 4 –2,8‐diaminoazelate via a copper catalyzed double S N 2′ addition of zincates derived from methyl β‐iodo alaninate onto ( E )‐1,3‐dichloroprop‐1‐ene, followed by stereoselective ring closures employing a facial selective iodolactonization 26 . The crystal structure of (3 S ,6 S ,7 S ,9 S )‐Boc‐(7‐hydroxy)I 2 aa‐OMe ( 17 ) revealed two conformers in the unit cell with respective ψ i + 1 and ϕ i + 2 dihedral angle values (−172° and −78°; −175° and −78°) which were similar to those of the unsubstituted (3 S ,6 S ,9 S )‐Boc‐I 2 aa‐OMe ( 9 : −176° and −78°), the bicycle of which is found in the most potent FP modulator (6 S )‐ 2 .…”

“…19 Recently, effective syntheses of (3S,5S,6S,9S)-Boc-(5-hydroxy) I 2 aa-OH (15) and (3S,6S,7S,9S)-Boc-(7-hydroxy)I 2 aa-OH [16,Figure 3] were achieved by a route involving the construction of a Δ 4 -2,8-diaminoazelate via a copper catalyzed double S N 2 0 addition of zincates derived from methyl β-iodo alaninate onto (E)-1,3-dichloroprop-1-ene, followed by stereoselective ring closures employing a facial selective iodolactonization. 26 The crystal structure of (3S,6S,7S,9S)-Boc-(7-hydroxy)I 2 aa-OMe (17) revealed two conformers in the unit cell with respective ψ i + 1 and ϕ i + 2 dihedral angle values (À172 and À78 ; À175 and À78 ) which were similar to those of the unsubstituted (3S,6S,9S)-Boc-I 2 aa-OMe (9: À176 and À78 ), the bicycle of which is found in the most potent FP modulator (6S)-2. Although crystals of analogs of Boc-(5-hydroxy)I 2 aa-OH 15 have yet to be obtained, the related o-NBS-(5-iodo)I 2 aa-OMe (18) has been characterized in the solid state by X-ray and shown to have internal ψ i + 1 and ϕ i + 2 dihedral angle values (À127 and À65 ), 24 The uterus was obtained immediately from CD-1 mice after term delivery under anesthesia (2.5% isoflurane).…”